CA1146534A

CA1146534A - Hydrocortisone esters, pharmaceutical formulations containing these and processes for their preparation

Info

Publication number: CA1146534A
Application number: CA000339427A
Authority: CA
Inventors: Manfred Baumgarth; Dieter Orth; Jurgen Harting
Original assignee: Merck Patent GmbH
Current assignee: Merck Patent GmbH
Priority date: 1978-11-08
Filing date: 1979-11-08
Publication date: 1983-05-17
Also published as: US4264585A; IL58639A; DE2848423A1; JPS5569599A; ATE970T1; EP0011121A1; DE2962721D1; AU5257479A; EP0011121B1; ZA795986B; ES485784A1; HU180874B; IL58639A0; AU531242B2

Abstract

ABSTRACT OF THE DISCLOSURE

Hydrocortisone esters of the formula

Description

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The present invention relates to new hydrocortisone esters.
An object of this invention is to provide new compounds having valuable properties, especially those which can be used for the preparation of medicaments.

These objects have been attained by providing new hydro-cortisone esters of Formula I
O--CO-C (CH3) R -OCOCH3 ~ , .
O ~

wherein R is H, formyl or acetyl and R is H or CH3.

In Formula I, R is preferably H or acetyl. R is preferably 10 H. Accordingly, the invention relates in particular to those com-pounds of Formula I in which at least one of Rl and R2 has one of these preferred meanings.
The present invention also relates to a process for the preparation of the compounds of Formula I, comprising 15 reacting a steroid of Formula II

~, OR
HO~
,~,J.~ ~ I I

114~53~

wherein Rl is as defined above, or a functionally modified derivative thereof, with a 2~hydroxy-fatty acid of Formula III

CH3-CR (OH)-COOH III

wherein R is as defined above, or with a functionally modified derivative thereof, and, for those resultant compounds having an OH in the substituent in the 21-position, acetylizing this OH groupO
In other respects, the hydrocortisone esters of Formula I
are prepared by methods which are in themselves known, such as those described in the literature (for example in the standard works such as Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg-Thieme-Verlag, Stuttgart and Organic Reactions, John Wiley and Sons, Inc., New York) and, specifically, under reaction conditions which are known and suitable for these reactions. Use can also be made of variants which are in them-selves known and are not mentioned in more detail herein.
Functionally modified derivatives of the steroids of Formula II include preferably the corresponding 21-iodide compounds or the 21-methane-sulfonates and also the 21-p-toluenesulfonates;
Functionally modified derivatives of the compounds of Formula III
include preferably the corresponding carboxylic acid halides, especially the chlorides and bromides, and the corresponding acid anhydrides, and also the corresponding deriva-tives containing an acetylated hydroxyl group on C(2).
The compounds III can be racemic or optically active.
Accordingly, the compounds of Formula I include those forms which are racemic and optically active in respect of the asymmetric C
atoms in the substituent in the 21-position.

The steroids of Formula II are preferably reacted with acids of the formula CH3-CR (OCOCH3)-COOH (IIIA) or the derivatives thereof which are functionally modified at the carboxyl group, such as, for example, the halides (for example chlorides) or 5 anhydrides thereof, appropriately at temperatures of -100 to +200C and preferably about -20 to +150C. The reaction times vary from about 1 minute to 48 hours and preferably 10 minutes to 24 hours.
When one of the above mentioned acids IIIA is employed as 10 the esterifying agent, the reaction can be carried out without or with the addition of catalysts, such as sulfuric acid, hydrogen chloride, phosphoric acid, aromatic sulfonic acids, such as p-toluenesulfonic acid, or acid ion exchangers, and, in particular, preferably at temperatures of 10 to 150 C. The acid IIIA lS
15 usually employed in excess.
The reaction can also be carried out in the presence of water-binding agents, for example molecular sieves or anhydrous heavy metal sulfates, such as copper sulfate, iron sulfate, nickel sulfate, cobalt sulfate or zinc sulfate. The water formed during 20 the esterification can also be removed by azeotropic distillatio~, and hydrocarbons, such as benzene or toluene, or chlorinated hydrocarbons, such as chloroform or 1,2-trichloroethane, are advantageously added as inert organic solvents.
Under very mild conditions, the esterification proceeds 25 if the water of reaction is bonded chemically by the addition of carbodiimides, such as N,N'-dicyclohexylcarbodiimide, preferably in molecular amounts, the reaction being carried out in inert solvents such as ether, dioxane, benzene orethylene glycol dimethyl ether, or preferably in bases such as pyridine.

114653~
The steroids of Formula II can also be reacted with func-tionally modified derivatives of the acids IIIA, for example with their halides or anhydrides, without or with the addition of acid-binding agents, for example of sodium hydroxide or potassium hydroxide, sodium carbonate or potassium carbonate, or of an organic base such as pyridine, quinoline, collidine or trie.thyl-amine. Suitable solvents include inert organic solvents, such as ether, tetrahydrofuran or benzene. It is also possible to use excess halides or anhydrides or an excess of the base as the solvent. The esterification reaction is approximately carried out at temperatures of -20 to 150C and preferably 0 to 30C
and as a rule takes 10 minutes to 24 hours.
It is also possible to use functionally modified derivatives of the steroids II as the starting materials and, in particular, to use the corresponding 21-iodosteroids. These are produclble by reacting the steroids II with methanesulfonyl chloride to give the corresponding 21-methanesulfonyloxy-steroids and subsequently replacing the methanesulfonyloxy group by iodine. The 21-iodo-steroids are preferably reacted with the carboxylic acids III
or IIIA in the presence of amines such as triethylamine or pyri-dine, or also with the salts of these carboxylic acids, for example, the alkali metal, alkaline earth metal, magnesium,zinc or ammonium salts, preferably the sodium or potassium salts.
The reaction is as a rule carried out in the presence of an inert solvent, such as acetone or ether. The reaction temperatures are about 40 to 120C and preferably 40 to 70C; the reaction times are about 1 to 15 hours and, in general, 5 to 10 hours.

_. . .. . .

1146S3~

, If the resultiny product still contains a free hydroxyl group in the substituent in the 21-position, this group is su~sequently acetylated by a conventional mild acetylation method. This can be effected, for example, by reaction with an excess oE acetic anhydride in pyridine at room temperature. During the acetylation, the less reactive hydroxyl group in the ll-position of the hydro-cortisone is not attacked.
: It has been found that the compounds of Formula I
possess valuable pharmacological properties coupled with good tolerance. In particular, antiphlogistic effects are displayed which can be ascribea, for example, to an anti-proliferative active component (detectable, for example, analogously to the method of Rudas, Drug Research 10, 226 (1969)), an antiexsudative active component (detectable, for example, analogously to the method described by ~otovy and Kapff, Arch. Int. Pharmacodyn., 111, 420-436 (1957);
granuloma pouch' test), a thymolytic active component (detectable, for example, analogously to the method of Steelman et al, Steroids 1, 163 (1963)), and an active component which inEluences the ~CTII (detectable on the basis of the inhibition of an adrenal hypertrophy analo-gously to ~le method of ~ohus, B., ~cta Physiol. ~cad.
Sci. Hung. 29, 203 (1966)). The compounds of Formula I
are thereEore suitable, for example, for combating persis-tent allergies and other inflammatory diseases of the skin and also for the treatmcnt of rheumatic arthritis. 'These' actions are detectable by the test methods conventional for this purpose.

~__ ., ,. . . . .... . . __ 53~

The compounds of Formula I can therefore be used as medicinally active compounds for treating patients in human medicine and, e.g., mammals, in veterinary medicine and can also be used as intermediates for the preparation of other medicinally active compounds.
The present invention, thus, also relates to the use of the new compounds of Formula I for the preparation of pharmaceutical formulations, especially by a non-chemical route. The compounds I can be brought into a suitable dosage form together with at least one solid, liquid and/or semi-liquid excipient or auxiliary and, optionally, in combination with one or more additional active compounds.
The present invention also relates to agents, especially pharmaceutical formulations, containing a-t least one com-pound of Formula I.
These formulations can be used as medicaments in humanmedicine and in veterinary medicine. Excipients which are suitable include organic or inorganic substances which are particularly suitable for topical application and do not react with the new compounds, for example water, vegetable oils, hydrocarbons such as alkylated naphthalenes, halogenated hydrocarbons such as CF2C12 (for example, for aerosols), benzyl alcohols, polyethylene glycols, gly-cerol triacetate, gelatin, carbohydrates, such as lactose or starch, magnesium stearate, talc and petroleum jelly.
The formulations used for topical application include in particular solutions, lo-tions, emulsions, sprays (aerosols), ointments, creams, pastes or powders. The new compounds can also be lyophilized. The indicated formulations can be sterilized and/or contain auxiliaries such as lubricants, preservatives, stabilizers and/or ~14~53~

wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, dyes and/or aroma generating substances. They can, if desired, also contain one or more additional active compounds, for example, one or more antibiotics, such as gentamycin and/or anti-mycotics and/or other substances having a topical action.
The new compounds are as a rule administered analogously to known anti-inflammatory agents available commercially (for example hydrocortisone 17-butyrate). For topical application in combination with excipients suitable for this purpose, a good activity can be determined over relatively wide dilution ranges.
For example, concentrations of the active compound of about 0.05 to 1 percent by weight, based on the weight of the preparation used, are effective for healing inflammations Concentrations of about 0.1 to 0.5 percent by weight are preferred.
For oral or parenteral administration, the daily dosage is gene~ally about 0.01 to 1 mg/kg of body weight.
20 Unit dosages are about 0.5 to 50 mg, preferably S to 25 mg.
Each of the compounds of the Formula I named in the examples which follow is particularly suitable for the preparation of pharmaceutical formulations.

1~6S34 Without further elaboration, it is believed that one skllled in the ~rt can, using the preceding descrip-tion, utilize the present invention to its fuIlest extent.
The following preferred specific embodiments are, therefore, tobe construed as merely illustrative.

In the following examples, all temperatures are set forth uncorrected in degrees Celsius; unless otherwise indicated, all parts and percentages are by weight.
EX~IPLE 1 11.16 g of acetyllactic acid chloride is added drop-wise, with the exclusion of moisture, at 0 to 5, to a solution of 10 g of hydrocortisone 17-acetate in 100 ml of pyridine; the mixture is.stirred for one hour at 20 and then poured into 5~ ice-cold hydrochloric acid, and .
the precipitate is extracted with methylene chloride. The extract is washed with water, saturated sodium bicarbonate solution and water and dried over sodium sulfate. Evapo-ration and chromatography of the residue on silica gel (solvent system: methylene chloxide/petroleum ether/
acetone 10:10:3) gives hydrocortisone 17-acetate 21-(2-acetoxypropionate) of m.p. 115-117 (from ether); 1~]20=
64.2 (CHC13).
EX~PLES 2 to 6 _ .
The fol.lowing compounds are obtained analogously to EX~MPLE 1 from hydrocortisone, hydrocortisone 17-formate or hydrocortisone 17-acetate Witil acetyllactic acid chloride or 2-acetoxy-isobuty~ic acid chloride:

_~_ . . -- _ .

- 1~L46S3~

2. Hydrocortisone 17-acetate 21-(2-acetoxyisobutyrate), m.p. 114-117 (from acetone).

3. Hydrocortisone 21-(2-acetoxypropionate~, m.p. 182 -183 (from acetone); [~]D = +185.1 (CHC13).

4. Hydrocortisone 21-(2-acetoxyisobutyrate), m.p. 180 -181 (from acetone/ether/petroleum ether).

5. Hydrocortisone 17-formate 21-(2-acetoxypropionate).

6. Hydrocortisone 17-formate 21-(2-acetoxyisobutyrate).

170 g of acetyllactic anhydride [b.p. 107 under 0.01 mm Hg; can be prepared by reacting lactic acid with acetyl chloride and subsequently treating the resulting acetyllactic acid (b.p. 110 under 5 mm Hg) with dicyclohexylcarbodiimide in ether] is added, with the exclusion of moisture, to 188.8 g of hydrocortisone 17-acetate in 144 ml of pyridine and the mixture is left to stand for 2 hours at 20. The mixture is poured into ice-water and extracted with methylene chloride. The extract is washed with water, 10% hydrochloric acid, saturated sodium bicarbonate solution and water and dr:ied over sodium sulfate.
Evaporation yields hydrocortisone 17-acetate 21-(2-acetoxy-propionate), m.p. 115-117 C (from ether); [~]D = ~64.2 (CHC13).

8 g of acetyllactic acid and then 4 g of dicyclohexyl-carbodiimide are added to 4 g of hydrocortisone 17-acetate in 80 ml of pyridine; the mixture is stirred for 20 hours with the exclusion of moisture; and the product which has precipitated is filtered off. Water is added to the filtrate _g_ 1~L4653~

and the mixture is acidified with dilute hydrochloric acid and then extracted with ethyl acetate. The organic phase is washed with sodium bicarbonate solution an~l water, dried over sodium sulfate and evaporated, and hydrocortisone 17-acetate 21-(2-acetoxypropionate) is obtained; m.p. 115 -117 (from ether); [~D =+~4.2 (CIIC13).
EXAMPL~ 9 A solution of 23.5 g of 21-dehydroxy-21-iodohydro-cortisone (obtained by the action of methanesulfonyl chloride . 10 on hydrocortisone and subsequent reaction of the resulting hydrocortisone 21-methanesulfonate with sodium iodide in acetone), 6.6 g of acetyllactic acid and ~.8 ml of triethylamine in 1,000 ml of acetone is boiled for 7 hours and then evaporated to about half its volume. The solution is poured into water and neutralized and the resulting hydrocortisone 21-(2-acetoxypropionate) is filtered off;
m.p. 115 - 117 (from ether); L~]D =+64-2 (CIIC13).
~XAMPLE 10 A solution of 23.5 g of 21-dehydroxy-21-iodohydro-cortisone, 4.5 g of lactic acid anci 8.8 ml of triethylamine in 1,000 ml of acetone is reacted, and worked up, analogously to Example 9. The crude hydrocortisone 21-(2-hydroxy-propionate) is then left to stand with 200 ml of dry pyridine and 100 ml of acetic anhydride for 3 hours at 25.
The mixture is then stirred into ice-water, the precipitate is isolated and hydrocortisone 21-~2-acetoxypropionate) is obtained; m.p. 115 - 117 (from ether); 1~2 =+G4.2 (CIIC13) The examples which follow relate to pharmaceutical formulations which contain compounds of the Formula I
(percentages are percentages by weight).
EXAMPLE A: OINTMENT

. . . _ Hydrocortisone 17-acetate 21~
(2-acetoxy-propionate) 0.25%

Anhydrous wool fat 2.0 %

Viscous paraffin 10.0 %

White petroleum jellyto make up to 100.0 %

EXAMPLE B: CREAM

Hydrocortisone 17-acetate 21-(2-acetoxy-propionate) 0.5 %

Cetyl alcohol 9.0 %

Viscous paraffin3.0 %

Glycerol monostearate 2.0 %

Propylene ylycol monostearate 2.0 %

Glycerol 2.0 Very finely divided silica 0.1 ~

Petroleum jelly10.0 %

Polyoxyethylenesorbitane monopalmitate 30.0 %

Methyl p-hydroxybenzoate 0.065 Propyl p-hydroxybenzoate 0.035 Propylene glycol3.0 %

Waterto make up to 100.0 %

EXAMPLE C: LOTION

Hydrocortisone 17-acetate 21-(2-acetoxy-propionate) 0.2 %

Viscous paraffin oil 10.0 ~

Ethanol 2.0 %

, Glycerol 1.0 %

~4653~

Propylene glycol 2.0 ~
Sorbic acid 0.15%
Fatty alcohol polyglycol ether 2.0 Mixture of cetylstearyl alcohol and sodium cetylstearylsulfate and a non-ionic emulsifier 0.5 ~
Perfume oil of lily-of-the-valley 0.01%
Water to make up to 100.0 EXAMPLE D: OINTMENT
_ _ Hydrocortisone 17-acetate 21-(2-acetoxy-propionate) - 0.1 %
Gentamycin sulfate (based on free gentamycin base 0.1 Cetyl alcohol 2.4 ~
Anhydrous wool fat 1.0 %
Viscous paraffin 15.0 White petroleum jelly to make up to 100.0 ~
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

-'

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the production of a hydrocortisone ester of the formula wherein R1 is H, formyl or acetyl and R2 is H or CH3, which comprises reacting a steroid of the formula II

wherein R1 is as defined above or a functionally modified derivative thereof with a 2-hydroxy-fatty acid of the formula CH3-CR2(OH)-COOH
wherein R2 is as defined above, or with a functionally modified derivative thereof, and, for those resultant compounds having an OH in the substituent in the 21-position, acetylizing this OH group.

2. A process for the production of hydrocortisone 17-acetate 21-(2-acetoxypropionate) which comprises reacting hydrocortisone 17-acetate with acetyllactic acid, its chloride or its anhydride.

3. A hydrocortisone ester of the formula wherein R1 is H, formyl or acetyl and R2 is H or CH3, whenever produced according to the process of Claim 1 or an obvious chemical equivalent thereof.

4. Hydrocortisone 17-acetate 21-(2-acetoxypropionate), a compound of Claim 3, whenever produced according to the process of Claim 2 or an obvious chemical equivalent thereof.